SUMMARY Our overarching goal for the University Texas PDX Development and Trial Center (UTPDTC) is to optimize personalized biomarker-based cancer therapy and identify effective targeted drugs based on the molecular characteristics of each tumor. Our short-term goals are to establish a biobank of clinically, and molecularly- annotated PDXs and to use PDXs as a platform for preclinical drug development and biomarker discovery. The primary goal for UTPDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations. These models will allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly defined subsets of tumors. In this application we propose projects to prioritize the clinical testing of many targeted agents focused on non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer (PDAC), and triple negative breast cancer (TNBC) tumor subtypes, as well as patients with selected genomic alterations across other histologies. Over the past 9 years, both University of Texas MD Anderson (UTMDACC) and The University of University of Texas Southwestern Medical Center (UTSW) have established institution-wide efforts to generate novel PDX models and perform preclinical testing. Cumulatively the two institutions have hundreds of PDX models of different tumor types, including clinically-annotated models in non-small cell lung cancer (NSCLC, n=190 with 150 at UTMDACC and 40 at UTSW), colorectal cancer (CRC, n=127 models) pancreatic adenocarcinoma (PDAC, n=145 models), and triple negative breast cancer (TNBC, n=44 models); four diseases where there is an urgent need for novel therapeutics. We have characterized many tumor subtypes in our existing PDXs and plan to characterize many more with the ultimate goal of developing drug combinations in defined tumor subsets in a context that can lead to clinical trials which will validate the experimental results. We plan to focus on NCI-IND agents that are primarily used by the Experimental Therapeutics Clinical Trials Network. The availability of hundreds of PDXs of diverse histologic types and molecular profiles provides a unique opportunity for synergistic interactions among the UTPDTC investigators, PDXNet, and ETCTN. Each Project will identify molecular subtypes and then test with drugs targeted to putative pathways. Similar molecular subtype profiles will be identified across projects and histologic classifications. This provides an opportunity to test the activity of drugs targeting specific molecular pathways that may be active in several histologically distinct subtypes. Such pan-histologic activity could greatly accelerate drug development. Our proposed studies focus on targeted therapeutic agents for treatment of diseases and/or molecular subtypes that have unmet medical needs. The proposed studies are highly relevant to public health, as their success will lead to effective precision therapy for cancers, for which current therapies are ineffective.